ERK/MAPK regulates ERRγ expression, transcriptional activity, and receptor-mediated Tamoxifen resistance in ER+ breast cancer
| Autor: | Mary M. Heckler, Rebecca B. Riggins, Hemang Thakor, Cara C. Schafer |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
Selective Estrogen Receptor Modulators medicine.medical_specialty Antineoplastic Agents Hormonal medicine.drug_class MAP Kinase Signaling System Estrogen receptor Breast Neoplasms Biology Biochemistry Article Internal medicine medicine Humans RNA Messenger RNA Neoplasm skin and connective tissue diseases Protein kinase A Molecular Biology Kinase Cell Biology Recombinant Proteins Gene Expression Regulation Neoplastic Tamoxifen Endocrinology Nuclear receptor Receptors Estrogen Estrogen Selective estrogen receptor modulator Drug Resistance Neoplasm Cancer research MCF-7 Cells Mutagenesis Site-Directed Female hormones hormone substitutes and hormone antagonists medicine.drug |
| Popis: | Selective estrogen receptor modulators such as tamoxifen (TAM) significantly improve breast cancer-specific survival for women with estrogen receptor-positive (ER+) disease. However, resistance to TAM remains a major clinical problem. The resistant phenotype is usually not driven by loss or mutation of the estrogen receptor; instead, changes in multiple proliferative and/or survival pathways over-ride the inhibitory effects of TAM. Estrogen-related receptor γ (ERRγ) is an orphan member of the nuclear receptor superfamily that promotes TAM resistance in ER+ breast cancer cells. This study sought to clarify the mechanism(s) by which this orphan nuclear receptor is regulated, and hence affects TAM resistance. mRNA and protein expression/phosphorylation were monitored by RT-PCR and western blotting, respectively. Site-directed mutagenesis was used to disrupt consensus extracellular signal-regulated kinase (ERK) target sites. Cell proliferation and cell-cycle progression were measured by flow cytometric methods. ERRγ transcriptional activity was assessed by dual-luciferase promoter–reporter assays. We show that ERRγ protein levels are affected by the activation state of ERK/mitogen-activated protein kinase, and mutation of consensus ERK target sites impairs ERRγ-driven transcriptional activity and TAM resistance. These findings shed new light on the functional significance of ERRγ in ER+ breast cancer, and are the first to demonstrate a role for kinase regulation of this orphan nuclear receptor. |
| Databáze: | OpenAIRE |
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